Evaluation of the dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to TiO2, chrysotile, crocidolite or amosite asbestos in a 90-day quantitative inhalation toxicology study - Interim results Part 2: Histopathological examination, Confocal microscopy and collagen quantification of the lung and pleural cavity

Our plain-English summary of Evaluation of the dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to TiO2, chrysotile, crocidolite or amosite asbestos in a 90-day quantitative inhalation toxicology study - Interim results Part 2: Histopathological examination, Confocal microscopy and collagen quantification of the lung and pleural cavity, by D.M. Bernstein, B. Toth, R.A. Rogers, et al (Toxicology and Applied Pharmacology, 2020).

The study

• Authors: D.M. Bernstein, B. Toth, R.A. Rogers, D.E. Kling, P. Kunzendorf, J.I. Phillips, H. Ernst
• Journal: Toxicology and Applied Pharmacology
• Published: 2020;387:114847
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The interim results from this 90-day multi-dose, inhalation toxicology study with life-time post-exposure observation has shown an important fundamental difference in persistence and pathological response in the lung between brake dust derived from brake-pads manufactured with chrysotile, TiO2 or chrysotile alone in comparison to the amphiboles, crocidolite and amosite asbestos. In the brake dust exposure groups no significant pathological response was observed at any time. Slight macrophage accumulation of particles was noted. Wagner-scores, were from 1 to 2 (1 = air-control group) and were similar to the TiO2 group. Chrysotile being biodegradable, shows a weakening of its matrix and breaking into short fibers & particles that can be cleared by alveolar macrophages and continued dissolution. In the chrysotile exposure groups, particle laden macrophage accumulation was noted leading to a slight interstitial inflammatory response (Wagner-score 1-3). There was no peribronchiolar inflammation and occasional very slight interstitial fibrosis. The histopathology and the confocal analyses clearly differentiate the pathological response from amphibole asbestos, crocidolite and amosite, compared to that from the brake dust and chrysotile. Both crocidolite and amosite induced persistent inflammation, microgranulomas, and fibrosis (Wagner-scores 4), which persisted through the post exposure period. The confocal microscopy of the lung and snap-frozen chestwalls quantified the extensive inflammatory response and collagen development in the lung and on the visceral and parietal surfaces. The interim results reported here, provide a clear basis for differentiating the effects from brake dust exposure from those following amphibole asbestos exposure. The subsequent results through life-time post-exposure will follow.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

In plain English

This was a rat inhalation study, reported as interim results (Part 2) through 180 days, three months after exposure ended. Nine groups of rats breathed one of the following for 6 hours a day, 5 days a week, for 13 weeks: filtered air, dust from brakes made with chrysotile (three dose levels), titanium dioxide (TiO2) particles, chrysotile (two doses), crocidolite, or amosite asbestos. Four rats per group were assigned to lung histopathology and confocal microscopy. In the brake dust groups, lung Wagner scores were grades 1 and 2. At the end of exposure, 2 of 4 high-dose chrysotile rats were grade 4. Crocidolite and amosite rats were grade 4 at every time point. Their lungs were about 20% heavier than controls, and they had significantly more collagen in the lung and in the visceral and parietal pleura. Pleural collagen in these groups averaged 2.8 to 3.9 times control levels. The brake dust, TiO2 and chrysotile groups showed no significant collagen differences from controls. The authors concluded that the results differentiate brake dust effects from amphibole asbestos effects. Lifetime results are still to come.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Subchronic (90-day) inhalation toxicology study in rats with planned lifetime post-exposure observation; this paper reports interim histopathology and confocal microscopy results through 180 days (3 months post-exposure)
• Who was studied: Laboratory rats in 9 exposure groups; 4 rats per group were assigned to lung histopathology and confocal microscopy at sacrifices on days 45, 89 (end of exposure) and 180
• Exposure: Filtered air; brake dust from brakes made with chrysotile at low, mid and high dose (mean 2.42, 4.85 and 6.63 WHO fibers/cm3); TiO2 particle control (0.70 mg/m3); chrysotile 7H19 at 119 and 233 WHO fibers/cm3; crocidolite (Voorspoed mine) at 181 WHO fibers/cm3; amosite at 281 WHO fibers/cm3
• Main results:
  • Crocidolite (group 8) and amosite (group 9) rats had statistically significantly increased lung weight relative to body weight at 45, 89 and 180 days, about 20% heavier than controls
  • All brake dust groups had Wagner grades 1 and 2
  • High-dose chrysotile group: Wagner grade 3 at 45 and 180 days; at 89 days, 2 rats were grade 3 and 2 rats were grade 4
  • High-dose chrysotile group: very slight multifocal interstitial fibrosis in 2 of 4 rats, reported in the results section at 89 and 180 days (the discussion says 89 days only)
  • Crocidolite and amosite groups were Wagner grade 4 at all time points
  • On histopathology slides, the percentage of grid squares with fibrosis rose from 0.43% at 45 days to 1.05% at 180 days in the crocidolite group, and from 0.77% to 1.10% in the amosite group
  • Confocal lung collagen was not significantly different from controls in the brake dust, TiO2 and chrysotile groups
  • Confocal lung collagen was significantly increased over controls in the crocidolite and amosite groups at 45, 89 and 180 days (p less than 0.0001); the article reports the increase as ranging from 14 to 21% for crocidolite and 11 to 14% for amosite
  • Pleural collagen was not significantly different from controls in the brake dust, TiO2 or chrysotile groups
  • Crocidolite group: pleural collagen averaged 2.8 times control in the visceral pleura and 3.4 times control in the parietal pleura, over days 45, 89 and 180
  • Amosite group: pleural collagen averaged 3.9 times control in the visceral pleura and 3.0 times control in the parietal pleura
  • No mesothelial cell hyperplasia was seen in any group on histology
  • Mesothelial thickness did not differ significantly between groups through 180 days, although activated mesothelial cells were seen in crocidolite and amosite rats
• The authors' conclusion: The authors concluded that no significant pathological response was seen in the brake dust groups at any time, and that the interim results provide a clear basis for differentiating brake dust exposure from the effects of amphibole asbestos exposure
• Limitations the authors state:
  • The results are interim; results through the lifetime post-exposure period will be reported later
  • Histology cannot rule out focal mesothelial hypertrophy (activated mesothelial cells), which may only be recognizable by electron microscopy
  • The grid-based fibrosis quantification on histopathology slides records only the presence or absence of collagen in each square, not the total amount
  • Snap freezing caused some minor contraction of the lung, giving the visceral pleural surface a wavy appearance
  • Exposure concentrations were still orders of magnitude greater than exposures reported for humans

Topics

The National Library of Medicine indexes this study under subjects our site covers: Amosite, Chrysotile, Crocidolite.

Medical terms in this study, explained in our Lexicon: Dose-response relationship, Pleura, Chrysotile, Crocidolite, Amosite, Collagen, Pleural Cavity, Amphibole Group.

Related studies

• Evaluation of the exposure, dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to TiO2, chrysotile, crocidolite or amosite asbestos in a 90-day quantitative inhalation toxicology study - Interim results Part 1: Experimental design, aerosol exposure, lung burdens and BAL — D.M. Bernstein, B. Toth, et al. (2020)
• Final results from a 90-day quantitative inhalation toxicology study evaluating the dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to TiO2, chrysotile, crocidolite or amosite asbestos: Histopathological examination, confocal microscopy and collagen quantification of the lung and pleural cavity — D.M. Bernstein, B. Toth, et al. (2021)
• Evaluation of the dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to chrysotile or crocidolite asbestos in a 28-day quantitative inhalation toxicology study — D.M. Bernstein, B. Toth, et al. (2018)
• Evaluation of the fate and pathological response in the lung and pleura of brake dust alone and in combination with added chrysotile compared to crocidolite asbestos following short-term inhalation exposure — D.M. Bernstein, R.A. Rogers, et al. (2015)
• Quantification of the pathological response and fate in the lung and pleura of chrysotile in combination with fine particles compared to amosite-asbestos following short-term inhalation exposure — D.M. Bernstein, R.A. Rogers, et al. (2011)
• The pathological response and fate in the lung and pleura of chrysotile in combination with fine particles compared to amosite asbestos following short-term inhalation exposure: interim results — D.M. Bernstein, R.A. Rogers, et al. (2010)

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